Heterozygous activating variants in platelet‐derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile ...myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.(Ser493Cys), and the oldest known individual age 53 years. The KOGS phenotype includes characteristic facial features, tall stature, scoliosis, hyperelastic thin skin, lipodystrophy, variable intellectual and neurological deterioration, and abnormalities on brain imaging. Long‐term outcome is unknown. Our cases confirm the phenotypic spectrum includes progressive flexion contractures, camptodactyly, widely spaced teeth, and constriction rings. We also propose novel occasional features including craniosynostosis, ocular pterygia, anterior chamber cleavage syndrome, early osteoporosis, increased pigmentation, recurrent haematomas, predisposition to cellulitis, nail dystrophy, carpal tunnel syndrome, recurrent hypoglycaemia in infancy, joint dislocation, and splenomegaly. Importantly, we report fusiform aneurysm of the basilar artery in two patients. Complications include thrombosis and stroke in the oldest reported patient and fatal rupture at the age of 21 in the patient with the novel variant. We conclude that cerebrovascular complications are part of the phenotypic spectrum of KOGS and KOGS‐like disorders and suggest vascular imaging is indicated in these patients.
Exo1 is a member of the Rad2 protein family and possesses both 5′–3′ exonuclease and 5′ flap endonuclease activities. In addition to performing a variety of functions during mitotic growth, Exo1 is ...also important for the production of crossovers during meiosis. However, its precise molecular role has remained ambiguous and several models have been proposed to account for the crossover deficit observed in its absence. Here, we present physical evidence that the nuclease activity of Exo1 is essential for normal 5′–3′ resection at the Spo11-dependent
HIS4 hotspot in otherwise wild-type cells. This same activity was also required for normal levels of gene conversion at the locus. However, gene conversions were frequently observed at a distance beyond that at which resection was readily detectable arguing that it is not the extent of the initial DNA end resection that limits heteroduplex formation. In addition to these nuclease-dependent functions, we found that an
exo1-D173A mutant defective in nuclease activity is able to maintain crossing-over at wild-type levels in a number of genetic intervals, suggesting that Exo1 also plays a nuclease-independent role in crossover promotion.
Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal ...microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES).
In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly.
The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4–11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three 3·2% of 93 fetuses).
WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness.
UK Department of Health and Social Care and The Wellcome Trust.
Aims
A couple were referred for prenatal genetic testing at 31 weeks' gestation due to the presence of mild polyhydramnios and multiple central nervous system (CNS) abnormalities, including ...borderline ventriculomegaly, possible delayed sulcation, an enlarged cisterna magna and a small area of calcification around the posterior horns. Testing was initiated to identify any underlying genetic cause.
Materials and Methods
Rapid trio exome sequencing (ES) was performed on DNA extracted from parental blood samples and amniotic fluid.
Results
A pathogenic homozygous nonsense variant in KLHL7 (NM_001031710.2) associated with PERCHING syndrome (#617055) was identified.
Conclusion
Whilst there are detailed descriptions of the many postnatal phenotypes seen in these patients, there are few reports of features identified during pregnancy. This report is the first published prenatal diagnosis of PERCHING syndrome and provides further information on the associated fetal phenotypes.
Key points
What is already known about this topic?
PERCHING syndrome is a rare multisystem disorder caused by biallelic pathogenic variants in KLHL7.
Postnatal phenotypes are well characterised and include retinitis pigmentosa, respiratory distress and neurologic abnormalities.
Intrauterine growth retardation and polyhydramnios have been reported, however information regarding prenatal manifestations is limited.
What does this study add?
This report extends the prenatal phenotype to include neurological abnormalities.
To our knowledge, it is the first prenatally diagnosed case of PERCHING syndrome published in the literature.
To determine the diagnostic yield of combined exome sequencing (ES) and autopsy in fetuses/neonates with prenatally identified structural anomalies resulting in termination of pregnancy, ...intrauterine, neonatal, or early infant death.
ES was undertaken in 27 proband/parent trios following full autopsy. Candidate pathogenic variants were classified by a multidisciplinary clinical review panel using American College of Medical Genetics and Genomics (ACMG) guidelines.
A genetic diagnosis was established in ten cases (37%). Pathogenic/likely pathogenic variants were identified in nine different genes including four de novo autosomal dominant, three homozygous autosomal recessive, two compound heterozygous autosomal recessive, and one X-linked. KMT2D variants (associated with Kabuki syndrome postnatally) occurred in two cases. Pathogenic variants were identified in 5/13 (38%) cases with multisystem anomalies, in 2/4 (50%) cases with fetal akinesia deformation sequence, and in 1/4 (25%) cases each with cardiac and brain anomalies and hydrops fetalis. No pathogenic variants were detected in fetuses with genitourinary (1), skeletal (1), or abdominal (1) abnormalities.
This cohort demonstrates the clinical utility of molecular autopsy with ES to identify an underlying genetic cause in structurally abnormal fetuses/neonates. These molecular findings provided parents with an explanation of the developmental abnormality, delineated the recurrence risks, and assisted the management of subsequent pregnancies.
Exo1 is a member of the Rad2 protein family and possesses both 5’-3’ exonuclease and 5’ flap endonuclease activities. In addition to performing a variety of functions during mitotic growth, Exo1 is ...also important for the production of crossovers during meiosis. However, its precise molecular role has remained ambiguous and several models have been proposed to account for the crossover deficit observed in its absence. Here, physical evidence that the nuclease activity of Exo1 is essential for normal 5’-3’ resection at the Spo11-dependent HIS4 hotspot in otherwise wild-type cells is presented. This same activity was also required for normal levels of gene conversion at the locus. Nevertheless, gene conversions were frequently observed at a distance beyond that at which resection was readily detectable arguing that it is not the extent of the initial DNA end resection that limits heteroduplex formation. In addition to these nuclease-dependent functions, nuclease-deficient exo1 mutants were found to be capable of maintaining crossing-over at wild-type levels in a number of genetic intervals, suggesting that Exo1 also plays a nuclease-independent role in crossover promotion. Furthermore, the results of both physical and genetic analyses imply that Sgs1 does not contribute significantly to resection during meiosis in exo1∆ cells, indicating that the mitotic and meiotic resection machinery differs. In light of these new insights, a model describing the formation of heteroduplex DNA and crossovers during meiosis is proposed.
Exo1 is a member of the Rad2 protein family and possesses both 5’-3’ exonuclease and 5’ flap endonuclease activities. In addition to performing a variety of functions during mitotic growth, Exo1 is ...also important for the production of crossovers during meiosis. However, its precise molecular role has remained ambiguous and several models have been proposed to account for the crossover deficit observed in its absence. Here, physical evidence that the nuclease activity of Exo1 is essential for normal 5’-3’ resection at the Spo11-dependent HIS4 hotspot in otherwise wild-type cells is presented. This same activity was also required for normal levels of gene conversion at the locus. Nevertheless, gene conversions were frequently observed at a distance beyond that at which resection was readily detectable arguing that it is not the extent of the initial DNA end resection that limits heteroduplex formation. In addition to these nuclease-dependent functions, nuclease-deficient exo1 mutants were found to be capable of maintaining crossing-over at wild-type levels in a number of genetic intervals, suggesting that Exo1 also plays a nuclease-independent role in crossover promotion. Furthermore, the results of both physical and genetic analyses imply that Sgs1 does not contribute significantly to resection during meiosis in exo1∆ cells, indicating that the mitotic and meiotic resection machinery differs. In light of these new insights, a model describing the formation of heteroduplex DNA and crossovers during meiosis is proposed.
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